Method of treatment

ABSTRACT

USE OF 17-ACYLATES OF MELENGESTROL, SAID ACRYLATES HAVING FROM TWO TO ABOUT TEN CARBON ATOMS, INCLUSIVE, FOR TREATING MULTIPLE SCLEROSIS.

United States Patent 3,773,937 METHOD OF TREATMENT Margaret E. Greig, Kalamazoo, Mich., assrgnor to The Upjohn Company, Kalamazoo, Mich. No Drawing. Filed May 15, 1972, Ser. No. 252,973 Int. Cl. A61k 17/00 US. Cl. 424-243 7 Claims ABSTRACT OF THE DISCLOSURE Use of l7-acylates of melengestrol, said acylates having from two to about ten carbon atoms, inclusive, for treating multiple sclerosis.

BACKGROUND OF THE INVENTION Multiple sclerosis is a human disease of possible autoallergic etiology. In the advanced stages the classical clinical signs and symptoms can include paralysis, spastic movements of limbs, abnormalities of speech, and ocular abnormalities. These neurological signs and symptoms are apparently caused by the patchy destruction of the material known as myelin, a system of membranes wrapped in a spiral around the central component of the nerve, the axon. When the myelin sheath surrounding a nerve fiber breaks down, the current theory is that the conduction of impulses along the exposed fiber is disrupted and the resulting neurological disorders occur. The disease is often characterized by alternating exacerbation and remission of symptoms. Spontaneous remissions have been known to last for a number of years.

To this date there is no known effective treatment for multiple sclerosis. People afflicted with this disease generally die from the disease, the disease side effects, or from other illnesses to which people afflicted with multiple sclerosis appear to be more susceptible.

SUMMARY OF THE INVENTION The 17 acylates of 6 methyl 16 methylene-17ahydroxy 4,6 pregnadione 3,20 dione, said acylates having from two to ten carbon atoms, inclusive, can be used for the treatment of multiple sclerosis. From hereinafter the compounds used in the invention will be referred to as 17-acylates of melengestrol. The administration of melengestrol acetate or higher acylates to humans alfiicted with multiple sclerosis can inhibit the course of the disease by ameliorating the neurological signs and abnormal histology of the central nervous system, in some cases causing a steady nonspontaneous remission.

Therefore, in accordance with our invention, a method for treating multiple sclerosis is disclosed, which comprises systemically administering to a human afllicted with multiple sclerosis an anti-multiple sclerosis effective but non-toxic amount of a compound selected from the group consisting of 17-acylates of melengestrol, said acylates having from two to about ten carbon atoms, inclusive.

DETAILED DESCRIPTION OF THE INVENTION Melengestrol acetate, as represented below, and the higher acylates up to about ten carbon atoms, are prepared and characterized in US. Pat. No. 3,359,287.

3,773,937 Patented Nov. 20, 1973 Illustrative 17-acylates of melengestrol include the lower alkanoic acids, monocyclic aryl carboxylic acids, monocyclic aryl lower alkanoic acids, and cycloalkane carboxylic acids such as acetic, propionic, butyric, isobutyric, tert-butylacetic, valeric, isovaleric, caproic, caprylic, decanoic, cyclopentane-carboxylic, cyclohexane carboxylic, benzoic, toluic, ethylbenzoic, phenylacetic, phenylvaleric, phenylpropionic, cyclopentylpropionic acids and the like. The preferred acids are the lower alkanoic acids having from two to four carbon atoms, inclusive, most preferably acetic acid. The acids having .from five to ten carbon atoms, inclusive, are employed in the parenteral form primarily, for use as the water or oil soluble active forms for a depot-type effect. In considering this effect, other acids above ten carbon atoms and including the 17 carbon atom palmitic acid can be employed as well.

The aforementioned acylates of melengestrol are administered systemically solely or in combination with one another to persons afllicted with multiple sclerosis.

The compositions suited for oral administration include solid and liquid compositions. The solid oral compositions can be in the form of tablets, scored or unscored, coated and uncoated; capsules, hard and soft; powders; granules; pills (enteric coated tablets, capsules or pills); and the like. Solid diluents and carriers suited for such compositions are selected from the group consisting of liquids, carbohydrates, proteins and mineral solids. The liquid oral compositions can be in the form of dispersions, suspensions, elixirs and syrups.

Tablets contain the essential active ingredient in the required amount with pharmaceutically acceptable diluents, excipients, binders, disintegrators and lubricants. The essential active ingredient is preferably mixed with a carbohydrate diluent, for example, starch and lactose; a mineral solid, for example, terra alba (calcium sulfate) and dicalcium phosphate; or the like, to form a basic powder mixture. The said mixture can be granulated by wetting with a protein binder such as gelatin solution, a carbohydrate such as starch paste, syrup, and acacia mucilage; and screened. As an alternative to granulating, the mixture can be slugged and the slugs broken down into granules prior to formation of the tablets. A carbohydrate disintegrator, for example, cornstarch, is advantageously added at the time of forming the basic mixture. A lubricant, for example, a lipid such as stearic acid, a stearate salt and mineral oil; a mineral solid such as talc; and the like is used to prevent sticking of the mixture to the tablet-forming dies. The said tablets can be coated or uncoated. Suitable coatings include a sealing coat of shellac, a taste-disguising carbohydrate coating such as.

sugar and methyl cellulose, and a lipid polish coating of, for example, carnauba wax. The coating can comprise (a) lipid type coatings of a semi-permeable nature for delaying absorption of the essential active ingredient to provide sustained action, or (b) enteric substances such as styrene maleic acid copolymer and cellulose acetate phthalate to resist release of the essential active ingredient in the stomach and permit release in the upper intestine.

The capsules for oral use comprise the essential active ingredient in combination with a pharmaceutically acceptable diluent or excipient and a formed gelatin enclosure for the composition. The capsules can be in the form of soft capsules enclosing the active ingredient in the required amount with suitable diluents, for example, edible oils. The diluents for hard capsules comprise mineral solids, for example, talc, dicalcium phosphate, and the like; carbohydrates, for example, starch and lactose and, as required, lubricants, for example, stearate salts.

The powders can be advantageously and conveniently prepared by comminuting the essential active ingredient in the required amount and mixing with a pharmaceutically acceptable diluent; for example, an edible carbohydrate such as starch, advantageously including sweetening and flavoring agents, for example, sugar or saccharin and flavoring oils.

As set forth above, the liquid oral compositions can be in the form of dispersions, suspensions, elixirs, and syrups.

Dispersions can be prepared in glycerol, propylene glycol, liquid polyethylene glycols, and mixtures thereof, and in edible oils. Under ordinary conditions of storage and use such preparations contain a preservative to prevent the growth of microorganisms. Likewise, sweetening, coloring, and flavoring agents can be added.

Suspensions are prepared in an aqueous vehicle containing diluents, flavors and preservatives as required.

The syrups contain the essential active ingredient in the required amount in an aqueous medium containing a sweetening agent, for example, sugar or saccharin. Colors, flavors, and preservatives are added for convenient storage and use.

As stated above, the pharmaceutical compositions can be in forms suited for injection use, which forms include sterile suspensions and solutions and sterile powders for the extemporaneous preparation of sterile injectable preparations. In all cases the form must be sterile and must be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The basic dispersion medium can contain water, ethanol, pharmaceutically acceptable polyols, for example, glycerol, propylene glycol, and liquid polyethylene glycol and the like, suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size for suspensions and by the use of surfactants, for example, a condensation product of ethylene oxide with fatty acids or fatty alcohols, partial esters of fatty acids and a hexitol anhydride, and polyoxyethylene condensation products of the esters. The deleterious action of microorganisms can be prevented by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, benzyl alcohol, phenol, sorbic acid, thimerosal, and the like. In many cases it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Although prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin, a preferred formulation for producing absorption over prolonged periods is an essentially aqueous suspension of melengestrol acetate of average particle sizebetween 20. and

Generally, suspensions are prepared by incorporating the previously sterilized essential active ingredient into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.

The essential active ingredient can be sterilized by the use of a gas, for example, ethylene oxide. With the required additional ingredients and in the proper particle size, the sterilized ingredient can be compounded into a sterile powder for later extemporaneous reconstitution with a desired suspending liquid which is sterile.

It is especially advantageous to compound the compositions in unit dosage form-for ease of administration and uniformity of dosage. Unit dosage form as used in the specification and claims herein refers to physically discrete units suited as unitary dosages for human subjects, each unit containing a predetermined quantity of active material calculated to produce the desiredtherapeutic effect in association with the required pharmaceutical carrier. Examples of the unit dosage forms heretofore described are tablets, capsules, pills,"powde r packets, wafers, cachets, teaspoonfuls, dropperfuls, and tablespoonfuls, implantable pellets or capsules, vials,'ampuls, and segregated multiples thereof, and other forms alluded to herein.

The following systemically admiriistereddosages can be employed in the treatment of multiple sclerosis. When employing an oral route of administratiomfrom about to about 350 mg. of compound can be administered daily, if desired, in up to four equal divided dosages per day for a period of at least eight weeks or longer, if toxic signs or symptoms remain absent. Responsewill vary With the individual patient. The parenteral administration includes intramuscular and intrathecal. When administered intramuscularly, the dosage should beqfrom about 1.0 to about 25 mg./kg./week in single or in divided doses administered up to 2 times per week. This can be continued for a period of up to about eight weeks or longer. Response will vary with the individual patient. In an alternative treatment regimen, the 1.0 to about 25 mg./kg, can be administered in a single monthly dose. When administered intrathecally, the compound is micronized, preferably to an average size of 0.5 to 10microns, and used at the same dosages as intramuscular.

The preferred route of administration is parenteral with the more preferred route intramuscular.

All doses must be related to variables including age, size, and sex of the patient involved. The dosage, as stated previously, includes any effective but non-toxic dosage. The toxic signs at which a physician would alter or stop treatment would depend upon the individual patient and the severity of the multiple sclerosis. It is possible that certain side effects, if not hazardous, will be more readily acceptable considering the nature of the disease bein treated.

The following examples are set forth to illustrate the invention and are not meant to limit the invention:

EXAMPLE 1 I H A patient afilicted with multiple sclerosis and exhibiting the following clinical symptoms; ocular abnormalities,

EXAMPLE 2 A patient afilicted with multiple sclerosis and exhibiting the following clinical symptoms: spastic movement of limbs, difiiculty with speech and loss of sphincter control is treated intramuscularly with 1400 mg. of melengestrol acetate per month in four to eight equally divided doses, for a period of three months.

During the course of treatment the spastic movement of the limbs is reduced, speech patterns are improved and some measure of control of the sphincter is regained. For a period of about three months after treatment is discontinued, the clinical symptoms gradually recur and treatment can be initiated again.

EXAMPLE 3 In a manner similar to Examples 1 and 2, patients afflicted with multiple sclerosis are treated with equivalent quantities of melengestrol propionate, melengestrol pphenylpropionate, melengestrol hexanoate, and melengestrol decanoate. Results similar to those achieved in Examples 1 and 2 are observed.

What is claimed is:

1. A method for treating multiple sclerosis which comprises systemically administering to a human afliicted with multiple sclerosis an anti-multiple sclerosis elfective but non-toxic amount of a compound selected from the group consisting of 17-acylates of melengestrol, said acylates having from two to four carbon atoms, inclusive.

2. A process in accordance with claim 1 wherein the compound is melengestrol acetate.

3. A method in accordance with claim 2 wherein the route of administration is selected from the group consisting of parenteral and oral.

4. A method in accordance with claim 3 wherein the administration is parenteral.

5. A method in accordance with claim 4 wherein the 6 dosage is from about 1.0 to about 25 mg./kg./week, administered intramuscularly.

6. A method in accordance with claim 3 wherein the administration is oral.

7. A method in accordance with claim 6 wherein the daily dosage is from about 100 mg. to about 350 mg.

References Cited UNITED STATES PATENTS 3,359,287 12/ 1967 Babcock et al 260-3974 OTHER REFERENCES Goldstein et al.: Trans. Am. Neurol. Assoc. 95 :243-4 (1970), Experimental Intrathecal Administration of Methylprednis'olone in Multiple Sclerosis.

Schmidt: Phychiat. Neurol. Med. Psychol. 19:152-6 (April 1967), Experience With Intrathecal corticosteroid Treatment of Polysclerosis and Other Neurological Diseases.

Mayer, K. et al.: Med. Welt. 10:392-5, Mar. 7, 1970, The Therapeutic Efiect of Corticosteroids on the Symptoms and Course of Multiple Sclerosis."

'Muller, 'E. et al.: Med. Welt. 91485-491, Mar. 4, 1967, Experience With Corticoid Long Term Therapy in Multiple Sclerosis.

Baker, A. 6.: Ann. Allergy 25 :665-672, December 1967, Intrathecal Methylprednisolone for Multiple Sclerosis.

Garde, A.: Lakartidningen 67:3307-8, July 15, 1970, Multiple Sclerosis Treatment With Steroids."

SHEP K. ROSE, Primary Examiner 

